Effects of chemoprotective agents on the metabolic activation of the carcinogenic arylamines PhIP and 4-aminobiphenyl in human and rat liver microsomes

Carcinogenic aromatic amines, including the heterocyclic amines, may pose a significant health risk to humans. To determine the potential for chemopro tective intervention against the carcinogenicity of these arylamines and to better understand their mechanism of action, a range of agents, most of th em natural dietary constituents, was examined in vitro for their ability to modulate the N-hydroxylation of 2-amino-1-methyl-6-phenylimidazo[4, 5-b]py ridine (PhIP) and 4-aminobiphenyl (ABP), an initial step in their bioactiva tion. Experiments were conducted with rat and human liver microsomes. The a gents (diallyl sulfide, indole-3-carbinol, alpha-angelicalactone, cafestol/ kahweol palmitates, cafestol, kahweol, benzylisothiocyanate, genistin, form ononetin, daidzin, equol, biochanin A, Oltipraz, tannic acid, quercetin, et hoxyquin, green tea, and black tea) comprised a variety of chemical classes that included sulfur-containing compounds, antioxidants, flavonoids, phyto estrogens, diterpenes, and polyphenols. Several of these agents, quercetin, ethoxyquin, and black tea, were found to strongly inhibit PhIP N-hydroxyla tion in rat liver microsomes, resulting in a nearly 85-90% decrease in acti vity at 100 mu M or 0.2%. Tannic acid and green tea, in addition to these a gents, were also strong inhibitors of ABP N-hydroxylation. In human liver m icrosomes, each of these agents was strongly inhibitory (approx 85-95% at 1 00 mu M or 0.02%) of PhIP and ABP N-hydroxylation. Theaflavins and polyphen ols were judged to be the primary inhibiting components in the teas, the th eaflavins showing the most potent effect These results demonstrate that che moprotective agents can inhibit the bioactivation of carcinogenic arylamine s, and this is likely to be one of the mechanisms of protection.